Evidence for complexation of P-450 IIC6 by an orphenadrine metabolite.
Removal of the orphenadrine metabolite from its complex with rat liver P-450 IIB1 is associated with a discrepancy in the reactivation of IIB1 activity. Two possible explanations are that either (1) NADPH-P-450-reductase is inaccessible to the restored IIB1, or (2) complexation of other P-450s may occur. Exogenous P-450 reductase increased all pathways of steroid hydroxylation (1.9 to 3.6-fold) but did not enhance reactivation of IIB1-dependent steroid 16 beta-hydroxylation. Instead, P-450 IIC6-dependent progesterone 21-hydroxylase activity was increased after dissociation to 122% of control. IIC6 activity was also inhibited in vitro in microsomes from phenobarbital-induced rats (ki = 151 microM). Thus, orphenadrine appears to complex P-450 IIC6 as well as IIB1 in rat liver.
Reidy
G F
GF
Department of Medicine, University of Sydney, Westmead Hospital, NSW, Australia.
Murray
M
M
D000735:Androstenedione / Q000378:metabolism; D000818:Animals; D019362:Cytochrome P-450 CYP2B1; D065607:Cytochrome P-450 Enzyme Inhibitors; D003577:Cytochrome P-450 Enzyme System / Q000378:metabolism*; D005292:Ferricyanides / Q000494:pharmacology; D007700:Kinetics; D008862:Microsomes, Liver / Q000201:enzymology*; D009966:Orphenadrine / Q000378:metabolism* / Q000494:pharmacology; D010088:Oxidoreductases / Q000378:metabolism; D010634:Phenobarbital / Q000494:pharmacology; D011374:Progesterone / Q000378:metabolism; D051381:Rats; D013250:Steroid Hydroxylases / Q000378:metabolism
D065607:Cytochrome P-450 Enzyme Inhibitors; D005292:Ferricyanides; D000735:Androstenedione; D011374:Progesterone; D003577:Cytochrome P-450 Enzyme System; D009966:Orphenadrine; D010088:Oxidoreductases; D013250:Steroid Hydroxylases; D019362:Cytochrome P-450 CYP2B1; C028033:potassium ferricyanide; D010634:Phenobarbital